Recently, the use of drug-eluting stents (DES) in percutaneous coronary interventions has received much attention. DES are medical devices that present or release bioactive agent into their surroundings (for example, luminal walls or coronary arteries). Generally speaking, bioactive agent can be coupled to the surface of a medical device by surface modification, embedded and released from within polymer materials (matrix-type), or surrounded by and released through a carrier (reservoir-type). The polymer materials in such applications should optimally act as a biologically inert barrier and not induce further inflammation within the body. However, the molecular weight, porosity of the polymer, a greater percentage of coating exposed on the medical device, and the thickness of the polymer coating can contribute to adverse reactions to the medical device.
Improved compatibility with blood is a desired feature for a variety of medical devices that contact blood during clinical use. The materials used for manufacture of medical devices are not inherently compatible with blood and its components, and the response of blood to a foreign material can be aggressive, resulting in surface induced thrombus (clot) formation. This foreign body response can in turn impair or disable the function of the device and, most importantly, threaten patient health. It is often desirable to modify the surface of medical devices, such as DES, to provide a biocompatible surface, to minimize or avoid such adverse foreign body responses.
As used herein, a surface of a medical article is characterized as “biocompatible” if it is capable of functioning or existing in contact with biological fluid and/or tissue of a living organism with a net beneficial effect on the living organism. Long-term biocompatibility is desired for the purpose of reducing disturbance of a host organism. One approach to improved biocompatibility for medical device surfaces is to attach various biomolecules such as antithrombogenic agents, anti-restenotic agents, cell attachment proteins, growth factors, and the like, to the surface of the device. For example, antithrombogenic agents can reduce the generation of substances as part of the clotting cascade, antirestenotic agents can reduce generation of aggressive scar tissue growth around the device, while cell attachment proteins can contribute to the growth of a layer of endothelial cells around the device.
Several benefits can be provided by biocompatible medical device surfaces. For example, such surfaces can increase patient safety, improve device performance, reduce adherence of blood components, inhibit blood clotting, keep device surfaces free of cellular debris, and/or extend the useable lifetime of the device.
One biomolecule that has been utilized to improve biocompatibility of medical device surfaces is heparin. Heparin is a pharmaceutical that has been used clinically for decades as an intravenous anticoagulant to treat inherent clotting disorders and to prevent blood clot formation during surgery and interventional procedures. Heparin molecules are polysaccharides with a unique chemical structure that gives them specific biological activity. When heparin is immobilized onto the surface of a medical device material, it can improve the performance of the material when in contact with blood in several ways: 1) it can provide local catalytic activity to inhibit several enzymes critical to the formation of fibrin (which holds thrombi together); 2) it can reduce the adsorption of blood proteins, many of which lead to undesirable reactions on the device surface; and 3) it can reduce the adhesion and activation of platelets, which are a primary component of thrombus.
In addition to heparin, other biomolecules that can be provided on a medical device to improve biocompatibility include extracellular matrix (ECM) proteins or ECM peptides derived from these proteins. Surfaces modified with appropriate proteins or peptides are less likely to be recognized as foreign than the original device surface and will promote the attachment and overgrowth of specific desirable cell types.
The preparation of biocompatible surfaces, however, can be challenging. This is particularly the case when attempting to provide biocompatibility to devices that also have other properties, such as DES. Materials that are used to form these coating may not be inherently compatible with each other, thereby making it difficult to form a coating that is both biocompatible and that has drug-releasing properties.
In addition, treatments that are used to form coatings can in some cases damage the bioactive agent and therefore reduce the overall effectiveness of the coated article. This may be the case when irradiation is used to form all or part of the coating. Irradiation sources can be useful for activating components of a coating composition to form the coating, but can also lack the specificity and therefore cause degradation of the bioactive agent that is present in the coating.
Another problem relates to the release of bioactive agent, as some materials release the bioactive agent immediately upon contact with tissue; therefore the bioactive agent is not present for an amount of time sufficient to provide a beneficial effect.